Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRAFFX2)

• DOT Name: Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4)
• Synonyms: PHGPx; EC 1.11.1.12; Glutathione peroxidase 4; GPx-4; GSHPx-4; EC 1.11.1.9
• Gene Name: GPX4
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Type-1/2 diabetes
  Adenocarcinoma
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  B-cell lymphoma
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Colorectal carcinoma
  Colorectal neoplasm
  Congestive heart failure
  Cryptorchidism
  Depression
  Fatty liver disease
  Glioma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Male infertility
  Multiple sclerosis
  Myocardial infarction
  Nasal polyp
  Non-small-cell lung cancer
  Pancreatic cancer
  Parkinson disease
  Spondylometaphyseal dysplasia, Sedaghatian type
  Squamous cell carcinoma
  Stroke
  Systemic lupus erythematosus
  Type-1 diabetes
  Lung adenocarcinoma
  Lung neoplasm
  Obesity
  Osteoarthritis
  Pulmonary fibrosis
  Renal cell carcinoma
  Hepatocellular carcinoma
  Melanoma
  Basal cell carcinoma
  Basal cell neoplasm
  Breast neoplasm
  Corpus callosum, agenesis of
  Neoplasm
• UniProt ID: GPX4_HUMAN
• PDB ID: 2GS3; 2OBI; 5H5Q; 5H5R; 5H5S; 6ELW; 6HKQ; 6HN3; 7L8K; 7L8L; 7L8M; 7L8Q; 7L8R; 7U4I; 7U4J; 7U4K; 7U4L; 7U4M; 7U4N
• EC Number: 1.11.1.12; 1.11.1.9
• Pfam ID: PF00255
• Sequence:
  MSLGRLCRLLKPALLCGALAAPGLAGTMCASRDDWRCARSMHEFSAKDIDGHMVNLDKYR
  GFVCIVTNVASQUGKTEVNYTQLVDLHARYAECGLRILAFPCNQFGKQEPGSNEEIKEFA
  AGYNVKFDMFSKICVNGDDAHPLWKWMKIQPKGKGILGNAIKWNFTKFLIDKNGCVVKRY
  GPMEEPLVIEKDLPHYF
• Function: Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins. Can also reduce cholesterol hydroperoxide and thymine hydroperoxide. Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation. Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species. The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis. The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures. May be required to protect cells from the toxicity of ingested lipid hydroperoxides. Required for normal sperm development and male fertility. Essential for maturation and survival of photoreceptor cells. Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion. Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism. Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway. Can reduce fatty acid-derived hydroperoxides. Can also reduce small soluble hydroperoxides such as H2O2, cumene hydroperoxide and tert-butyl hydroperoxide.
• Tissue Specificity: Present primarily in testis. Expressed in platelets (at protein level) .
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Ferroptosis (hsa04216)
• Reactome Pathway:
  (Name not found)
  Synthesis of 12-eicosatetraenoic acid derivatives (R-HSA-2142712)
  Synthesis of 15-eicosatetraenoic acid derivatives (R-HSA-2142770)
  Synthesis of 5-eicosatetraenoic acids (R-HSA-2142688)
• BioCyc Pathway: MetaCyc:HS09562-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Genetic Variation	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[6]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[6]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[7]
B-cell neoplasm	DISVY326	Strong	Biomarker	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Cryptorchidism	DISYUD2P	Strong	Biomarker	[13]
Depression	DIS3XJ69	Strong	Biomarker	[14]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[15]
Glioma	DIS5RPEH	Strong	Biomarker	[16]
Lung cancer	DISCM4YA	Strong	Altered Expression	[17]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[17]
Lymphoma	DISN6V4S	Strong	Altered Expression	[7]
Male infertility	DISY3YZZ	Strong	Biomarker	[18]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[19]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[20]
Nasal polyp	DISLP3XE	Strong	Genetic Variation	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[23]
Parkinson disease	DISQVHKL	Strong	Biomarker	[24]
Spondylometaphyseal dysplasia, Sedaghatian type	DISMKJPA	Strong	Autosomal recessive	[25]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[26]
Stroke	DISX6UHX	Strong	Genetic Variation	[27]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[28]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[29]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[30]
Lung neoplasm	DISVARNB	moderate	Biomarker	[30]
Obesity	DIS47Y1K	moderate	Altered Expression	[31]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[32]
Pulmonary fibrosis	DISQKVLA	moderate	Biomarker	[33]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[34]
Hepatocellular carcinoma	DIS0J828	Disputed	Altered Expression	[35]
Melanoma	DIS1RRCY	Disputed	Biomarker	[36]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[37]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[37]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[38]
Corpus callosum, agenesis of	DISO9P40	Limited	Altered Expression	[39]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4) decreases the response to substance of Hydrogen peroxide.	[72]
Camptothecin	DM6CHNJ	Phase 3	Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4) decreases the response to substance of Camptothecin.	[73]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[58]

27 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[41]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[42]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[43]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[44]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[45]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[46]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[47]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[48]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[49]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[50]
Artesunate	DMR27C8	Approved	Artesunate decreases the activity of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[51]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[53]
Trabectedin	DMG3Y89	Approved	Trabectedin decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[54]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[56]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[57]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Piperazinyl methyl quinazolinone derivative 2 decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[59]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[60]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[61]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[62]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[63]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[64]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[65]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[66]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[67]
Isoarnebin 4	DM0B7NO	Investigative	Isoarnebin 4 decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[68]
BUTEIN	DM8E54P	Investigative	BUTEIN decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[69]
ERIODICTYOL	DMD3BEQ	Investigative	ERIODICTYOL decreases the expression of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[71]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hesperetin	DMKER83	Approved	Hesperetin affects the binding of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[52]
carvacrol	DMINM2D	Investigative	carvacrol affects the binding of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[70]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tecfidera	DM2OVDT	Approved	Tecfidera increases the metabolism of Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4).	[55]

References

• [1] Plasma antioxidants, genetic variation in SOD2, CAT, GPX1, GPX4, and prostate cancer survival.Cancer Epidemiol Biomarkers Prev. 2014 Jun;23(6):1037-46. doi: 10.1158/1055-9965.EPI-13-0670. Epub 2014 Apr 7.
• [2] Glutathione peroxidase 4 functional variant rs713041 modulates the risk for cardiovascular autonomic neuropathy in individuals with type 1 diabetes.Diab Vasc Dis Res. 2019 May;16(3):297-299. doi: 10.1177/1479164118820641. Epub 2019 Jan 1.
• [3] Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo.PLoS One. 2019 Dec 4;14(12):e0225931. doi: 10.1371/journal.pone.0225931. eCollection 2019.
• [4] Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin.J Cell Physiol. 2020 Apr;235(4):3425-3437. doi: 10.1002/jcp.29232. Epub 2019 Sep 25.
• [5] Association of GPX1 and GPX4 polymorphisms with episodic memory and Alzheimer's disease.Neurosci Lett. 2018 Feb 14;666:32-37. doi: 10.1016/j.neulet.2017.12.026. Epub 2017 Dec 12.
• [6] Suppression of atherogenesis by overexpression of glutathione peroxidase-4 in apolipoprotein E-deficient mice.Free Radic Biol Med. 2008 Feb 1;44(3):343-52. doi: 10.1016/j.freeradbiomed.2007.09.009. Epub 2007 Oct 2.
• [7] Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma.Lab Invest. 2018 May;98(5):609-619. doi: 10.1038/s41374-017-0008-1. Epub 2018 Feb 20.
• [8] Lycium barbarum polysaccharide enhances development of previously-cryopreserved murine two-cell embryos via restoration of mitochondrial function and down-regulated generation of reactive oxygen species.J Reprod Dev. 2019 Apr 12;65(2):163-170. doi: 10.1262/jrd.2018-104. Epub 2019 Jan 31.
• [9] Sulfasalazineinduced ferroptosis in breast cancer cells is reduced by the inhibitory effect of estrogen receptor on the transferrin receptor.Oncol Rep. 2019 Aug;42(2):826-838. doi: 10.3892/or.2019.7189. Epub 2019 Jun 6.
• [10] MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure.Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1600-7. doi: 10.1152/ajpheart.01108.2009. Epub 2010 Mar 19.
• [11] RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer.Front Pharmacol. 2018 Nov 22;9:1371. doi: 10.3389/fphar.2018.01371. eCollection 2018.
• [12] Evidence that a polymorphism within the 3'UTR of glutathione peroxidase 4 is functional and is associated with susceptibility to colorectal cancer.Genes Nutr. 2007 Nov;2(2):225-32. doi: 10.1007/s12263-007-0052-3. Epub 2007 Oct 13.
• [13] Phospholipid hydroperoxide glutathione peroxidase is involved in the maintenance of male fertility under cryptorchidism in mice.Reprod Toxicol. 2015 Nov;57:73-80. doi: 10.1016/j.reprotox.2015.05.014. Epub 2015 Jun 4.
• [14] Variation of genes involved in oxidative and nitrosative stresses in depression.Eur Psychiatry. 2018 Feb;48:38-48. doi: 10.1016/j.eurpsy.2017.10.012. Epub 2018 Jan 10.
• [15] Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy.Mol Metab. 2015 Apr 21;4(6):493-506. doi: 10.1016/j.molmet.2015.04.001. eCollection 2015 Jun.
• [16] Gpx 4 is involved in the proliferation, migration and apoptosis of glioma cells.Pathol Res Pract. 2017 Jun;213(6):626-633. doi: 10.1016/j.prp.2017.04.025. Epub 2017 May 4.
• [17] STYK1/NOK correlates with ferroptosis in non-small cell lung carcinoma.Biochem Biophys Res Commun. 2019 Nov 19;519(4):659-666. doi: 10.1016/j.bbrc.2019.09.032. Epub 2019 Sep 18.
• [18] Mitochondrial glutathione peroxidase 4 disruption causes male infertility.FASEB J. 2009 Sep;23(9):3233-42. doi: 10.1096/fj.09-132795. Epub 2009 May 5.
• [19] Reduced expression of the ferroptosis inhibitor glutathione peroxidase-4 in multiple sclerosis and experimental autoimmune encephalomyelitis.J Neurochem. 2019 Feb;148(3):426-439. doi: 10.1111/jnc.14604. Epub 2018 Dec 3.
• [20] Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes.Cell Death Dis. 2019 Nov 4;10(11):835. doi: 10.1038/s41419-019-2061-8.
• [21] A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.Nat Genet. 2019 Feb;51(2):267-276. doi: 10.1038/s41588-018-0314-6. Epub 2019 Jan 14.
• [22] Erastin decreases radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis.Oncol Lett. 2019 Mar;17(3):3001-3008. doi: 10.3892/ol.2019.9888. Epub 2019 Jan 4.
• [23] Suppression of the malignant phenotype in pancreatic cancer by overexpression of phospholipid hydroperoxide glutathione peroxidase.Hum Gene Ther. 2006 Jan;17(1):105-16. doi: 10.1089/hum.2006.17.105.
• [24] Prioritized brain selenium retention and selenoprotein expression: Nutritional insights into Parkinson's disease.Mech Ageing Dev. 2019 Jun;180:89-96. doi: 10.1016/j.mad.2019.04.004. Epub 2019 Apr 15.
• [25] Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia. J Med Genet. 2014 Jul;51(7):470-4. doi: 10.1136/jmedgenet-2013-102218. Epub 2014 Apr 4.
• [26] Depletion of phospholipid hydroperoxide glutathione peroxidase up-regulates arachidonate metabolism by 12S-lipoxygenase and cyclooxygenase 1 in human epidermoid carcinoma A431 cells.FASEB J. 2003 Sep;17(12):1694-6. doi: 10.1096/fj.02-0847fje. Epub 2003 Jul 3.
• [27] The C718T polymorphism in the 3'-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension.Hypertens Res. 2012 May;35(5):507-12. doi: 10.1038/hr.2011.213. Epub 2011 Dec 8.
• [28] Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus.Mol Immunol. 2006 Mar;43(9):1497-507. doi: 10.1016/j.molimm.2005.07.039. Epub 2005 Sep 6.
• [29] Allelic variations in genes belonging to glutathione system increase proliferative retinopathy risk in type 1 diabetes individuals.Gene. 2019 Jun 30;703:120-124. doi: 10.1016/j.gene.2019.04.015. Epub 2019 Apr 5.
• [30] Effects of selenium supplementation on expression of glutathione peroxidase isoforms in cultured human lung adenocarcinoma cell lines. Lung Cancer. 2007 Jan;55(1):35-42.
• [31] Prepregnancy Obesity, Maternal Dietary Intake, and Oxidative Stress Biomarkers in the Fetomaternal Unit.Biomed Res Int. 2019 Jun 13;2019:5070453. doi: 10.1155/2019/5070453. eCollection 2019.
• [32] The hsa-miR-181a-5p reduces oxidation resistance by controlling SECISBP2 in osteoarthritis.BMC Musculoskelet Disord. 2018 Oct 5;19(1):355. doi: 10.1186/s12891-018-2273-6.
• [33] Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis.J Immunol. 2019 Oct 15;203(8):2076-2087. doi: 10.4049/jimmunol.1801232. Epub 2019 Sep 18.
• [34] Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014 Jan 16;156(1-2):317-331.
• [35] Impact of glutathione peroxidase 4 on cell proliferation, angiogenesis and cytokine production in hepatocellular carcinoma.Oncotarget. 2018 Jan 22;9(11):10054-10068. doi: 10.18632/oncotarget.24300. eCollection 2018 Feb 9.
• [36] Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles.Cancers (Basel). 2019 Jan 30;11(2):157. doi: 10.3390/cancers11020157.
• [37] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [38] Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer.J Clin Oncol. 2007 Jul 20;25(21):3015-23. doi: 10.1200/JCO.2006.10.0099.
• [39] Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis.Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22269-22274. doi: 10.1073/pnas.1912700116. Epub 2019 Oct 14.
• [40] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [41] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [42] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [43] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [44] Downregulation of Cx43 reduces cisplatin-induced acute renal injury by inhibiting ferroptosis. Food Chem Toxicol. 2021 Dec;158:112672. doi: 10.1016/j.fct.2021.112672. Epub 2021 Nov 13.
• [45] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [46] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [47] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [48] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [49] Effects of Se-depletion on glutathione peroxidase and selenoprotein W gene expression in the colon. FEBS Lett. 2005 Jan 31;579(3):792-6. doi: 10.1016/j.febslet.2004.12.042.
• [50] Chronic cyclophosphamide exposure alters the profile of rat sperm nuclear matrix proteins. Biol Reprod. 2007 Aug;77(2):303-11. doi: 10.1095/biolreprod.107.060244. Epub 2007 May 2.
• [51] Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 2019 Jan;109:2043-2053. doi: 10.1016/j.biopha.2018.11.030. Epub 2018 Nov 26.
• [52] Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner. Chem Biol Interact. 2023 Sep 1;382:110642. doi: 10.1016/j.cbi.2023.110642. Epub 2023 Jul 23.
• [53] Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008 Sep 15;45(6):763-72.
• [54] Trabectedin induces ferroptosis via regulation of HIF-1/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells. Chem Biol Interact. 2023 Jan 5;369:110262. doi: 10.1016/j.cbi.2022.110262. Epub 2022 Nov 14.
• [55] Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction. Cancer Sci. 2018 Sep;109(9):2757-2766. doi: 10.1111/cas.13701. Epub 2018 Jul 20.
• [56] Resveratrol protects against deoxynivalenol-induced ferroptosis in HepG2 cells. Toxicology. 2023 Aug 1;494:153589. doi: 10.1016/j.tox.2023.153589. Epub 2023 Jul 5.
• [57] Thioredoxin reductase is the major selenoprotein expressed in human umbilical-vein endothelial cells and is regulated by protein kinase C. Biochem J. 1999 Aug 15;342 ( Pt 1):111-7.
• [58] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [59] Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 2019 Sep 15;379:114665. doi: 10.1016/j.taap.2019.114665. Epub 2019 Jul 16.
• [60] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [61] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [62] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [63] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [64] Paraquat-induced ferroptosis suppression via NRF2 expression regulation. Toxicol In Vitro. 2023 Oct;92:105655. doi: 10.1016/j.tiv.2023.105655. Epub 2023 Jul 26.
• [65] Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.
• [66] Glutathione is a potential therapeutic target for acrolein toxicity in the cornea. Toxicol Lett. 2021 Apr 1;340:33-42. doi: 10.1016/j.toxlet.2021.01.005. Epub 2021 Jan 6.
• [67] Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis. Chem Biol Interact. 2023 Oct 1;384:110713. doi: 10.1016/j.cbi.2023.110713. Epub 2023 Sep 15.
• [68] Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation. Chem Biol Interact. 2023 Sep 1;382:110588. doi: 10.1016/j.cbi.2023.110588. Epub 2023 Jun 1.
• [69] Effects of butein on human osteosarcoma cell proliferation, apoptosis, and autophagy through oxidative stress. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221074346. doi: 10.1177/09603271221074346.
• [70] In vivo and In silico evidence of the protective properties of carvacrol against experimentally-induced gastric ulcer: Implication of antioxidant, anti-inflammatory, and antiapoptotic mechanisms. Chem Biol Interact. 2023 Sep 1;382:110649. doi: 10.1016/j.cbi.2023.110649. Epub 2023 Jul 25.
• [71] Eriodictyol regulated ferroptosis, mitochondrial dysfunction, and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer cells. J Biochem Mol Toxicol. 2023 Jul;37(7):e23368. doi: 10.1002/jbt.23368. Epub 2023 Apr 5.
• [72] Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem. 2004 Feb 27;279(9):7512-20. doi: 10.1074/jbc.M307677200. Epub 2003 Dec 3.
• [73] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.